1. No category

Optimizing Estrogen Replacement Treatment in Turner Syndrome
Robert L. Rosenfield, Nancy Perovic, Nancy Devine, Nelly Mauras, Tom Moshang,
Allen W. Root and Judy P. Sy
Pediatrics 1998;102;486
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/102/Supplement_3/486.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1998 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014
Optimizing Estrogen Replacement Treatment in Turner Syndrome
Robert L. Rosenfield, MD*; Nancy Perovic, RN, BSN*; Nancy Devine, RN, BSN*; Nelly Mauras, MD‡;
Tom Moshang, MD§; Allen W. Root, MDi; and Judy P. Sy, PhD#
ABSTRACT. Estrogen has a biphasic effect on growth,
stimulatory at low doses but inhibitory at higher doses.
Therefore, designing optimal sex hormone replacement
treatment in girls with Turner syndrome (TS) who are
being treated with growth hormone (GH) involves considering the dose and form of the estrogen as well as the
route and timing of its administration. We report here a
preliminary analysis of a study to test the concept that an
optimal estrogen replacement regimen should consist of
estradiol administered in a low dose by a systemic route.
The study population consisted of 9 girls with TS who
had been treated with GH for 6 or more months. When
the girls were 12 to 15 years old, we added depot estradiol
at a monthly intramuscular dose of 0.2 mg and increased
the dose at 6-month intervals to 0.4, 0.6, and, in 7 of the
girls, 0.8 mg. We compared the results in these subjects
with those in a matched group of 37 patients with TS in
whom routine estrogen treatment had been started at
similar ages and who were treated with a similar course
of GH therapy.
The gain in height at 2 years was 2.6 cm greater in those
who were treated with depot estradiol than in those who
were treated with routine estrogen. The bone age in the
patients who were treated with depot estradiol increased
in proportion to their chronologic age, suggesting that
this difference indicates an increase in their predicted
adult height. We conclude that using very low doses of
systemic estradiol to induce puberty before the age of 15
years in girls with TS who are treated with GH, instead
of using routine estrogen therapy, can result in increased
final heights. Pediatrics 1998;102:486 – 488; Turner syndrome, estrogen replacement, growth hormone, estradiol.
ABBREVIATIONS. GH, growth hormone; TS, Turner syndrome.
T
he secretion of estrogen during puberty contributes to the growth spurt of early puberty,1,2
with evidence for both indirect effects, which
are mediated by an increase in the secretion of
growth hormone (GH),3 and direct effects on cartilage growth.4 However, pharmacologic estrogen
treatment blunts growth,5 in part by attenuating the
action of GH.6 Determining the estrogen replacement
regimen that is optimal for use concurrently with GH
therapy has become a practical issue in the management of Turner syndrome (TS), which is characterized by both short stature and gonadal dysgenesis.
From the *Department of Pediatrics, University of Chicago, Chicago, Illinois; ‡Department of Pediatrics, Nemours Children’s Clinic, Jacksonville,
Florida; §Division of Endocrinology, University of Pennsylvania, Philadelphia, Pennsylvania; iDepartment of Pediatrics, University of South Florida,
Tampa, Florida; and #Department of Medical Affairs, Genentech Inc, South
San Francisco, California.
Received for publication Feb 6, 1998; accepted Mar 20, 1998.
Address correspondence to Robert L. Rosenfield, MD, Section of Pediatric
Endocrinology, University of Chicago Children’s Hospital, 5841 S Maryland
(M/C 5053), Chicago, IL 60637-1470.
PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Academy of Pediatrics.
486
SUPPLEMENT
A number of factors must be considered in designing optimal sex hormone replacement therapy in TS.
One is the timing of the estrogen administration.
Might delaying estrogen give endogenous or exogenous GH more time to act? This issue was addressed
recently by Attie and associates.7 Estrogen was
added to GH therapy in girls with TS at either 12 or
15 years of age, and the patients were followed from
12 years of age until near adult height. Estrogen was
given in the form of conjugated equine estrogens
(Premarin); the dosage was 0.3 mg/d for the first 6
months and then 0.6 mg/d with medroxyprogesterone acetate 10 mg/d added for 1 week each month.
The total growth from 12 years of age to near adult
height averaged 13.0 cm in the group in whom estrogen was begun at 12 years and 15.8 cm in those in
whom it was begun at 15 years; this difference was
highly significant. These investigators concluded
that delaying the initiation of estrogen therapy was
advantageous to growth.
Another consideration in optimizing the therapy is
the form of the estrogen. Estradiol is the natural form
of estrogen that is secreted and binds to the estrogen
receptor in humans.8 Ethinyl estradiol is an analogue
of estradiol with an ethinyl group covalently attached at the 17a position. Ethinyl estradiol is not
metabolized to estradiol but is taken up in unmodified form and retained by estrogen target tissues for
a longer time than is estradiol.9 The estradiol precursor estrone acts after being metabolized to estradiol.9,10 Equine estrogens, the major components of
the widely used drug Premarin, are not estradiol
precursors.
The route of estrogen administration also must be
considered. Estradiol is normally secreted into the
systemic circulation; thus, the liver receives the same
dose as other somatic tissues. In contrast, estrogen
given orally reaches the systemic circulation only
after absorption into the portal venous system and
after metabolism by the liver.11 In this situation, the
liver is exposed to a greater dose of estrogen than is
the rest of the body; thus, hepatic protein production
is affected disproportionately.12 Orally administered
estradiol is relatively ineffective systemically because
it is extensively metabolized by the liver to estrone
metabolites before it reaches the systemic circulation.
Ethinyl estradiol, estrogen sulfates, and equine estrogens are effective orally because they are relatively
protected from hepatic metabolism.
Finally, the estrogen dose must be considered. It is
well known that estrogen has a biphasic effect on
growth and that high doses inhibit growth and the
generation of somatomedin-C.6 These effects of estrogen have been taken advantage of in treating acromegaly13 and excessive stature,5 because they antagonize the effects of GH at the target organ level.
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014
On the other hand, low doses of estrogen stimulate
linear growth in hypogonadal girls. Depot estradiol
at a dose of 1 to 1.5 mg/mo stimulates growth during
puberty.1 Ethinyl estradiol at a dose of ;4 mg/d
stimulates the growth rate; at higher doses it inhibits
it.14
Physiologic considerations suggest that progestin
is unnecessary early in the induction of puberty.
Progesterone is not normally secreted by the ovary in
substantial amounts until a corpus luteum has
formed after ovulation has occurred. Furthermore,
half of all menstrual cycles are anovulatory for the
first 2 years after menarche. Therefore, progestin replacement appears not to be physiologic until after a
few years of estrogen treatment.
With these considerations in mind, we concluded
that an optimal hormone replacement regimen
would be estradiol administered in low doses by a
systemic route. We present here a preliminary analysis of data from a study of such a regimen in 9
patients with TS.
routine estrogen decreased significantly at each
6-month interval. Their mean height increased by 7.6
cm at 18 months and by 10.1 cm at 2 years. The
difference in height gained over the treatment period
was significant, with the girls who were treated with
depot estradiol having gained 1.4 cm more at 18
months than those who were treated with routine
estrogen and 2.6 cm more at 2 years (P , .001). Data
on the growth rates in the two groups are presented
in Table 1.
Additional analysis of the data on the girls who
were treated with depot estradiol showed that, on
average, their bone age increased by 1 year for every
year of treatment. As a consequence, their mean
height predicted by the Bailey–Pinneau method increased by 5.8 cm over the 2-year treatment period.
The entire increase took place in the first year after
treatment was begun. The height predicted after 2
years of depot estradiol therapy was not correlated
with the age at which the therapy was started.
METHODS
The growth rate in patients with TS who are
treated with GH can be expected to wane during
continued therapy,17 but in 7 of our 9 patients who
were treated concurrently with depot estradiol, the
growth rate actually increased in the first 6 months.
Furthermore, in 4 of the 9, it remained at or above
baseline after the first year. With depot estradiol,
their bone age increased at a normal rate, and, consequently, their height predicted by the Bayley–Pinneau method increased substantially, with this increase occurring during the first year of treatment.
The lack of correlation of age at initiation of therapy
with height potential at the end of 2 years of therapy
with depot estradiol suggests that very low dose
systemic estradiol possibly can be initiated at 12
years of age without any loss of height potential. In
contrast, initiating routine estrogen therapy at 12
years of age is associated with a loss of height potential.7 Therapy with depot estradiol led to an average of 2.6 cm more growth over a 2-year period than
did routine estrogen therapy, a highly significant
difference both statistically and in practical terms.
This difference is equivalent to that gained in about
1 year of GH therapy: during 6 years of GH therapy,
the mean height of patients with TS increased by 12
cm more than expected, with most of this gain coming in the early years of GH therapy.17
We enrolled 9 otherwise healthy patients with TS in a multicenter study at 12 to 15 years of age, after they had been treated
with GH for at least 6 months and had given informed consent.
They were given depot estradiol in gradually increasing doses
while their GH therapy was continued. The depot estradiol was
given as a single monthly intramuscular injection. An injection of
1.5 mg of depot estradiol causes cyclic changes in the levels of
estradiol in the blood; the levels peak at 4 to 7 days, and the drug
is undetectable by 3 weeks.15 We used smaller doses of depot
estradiol than have been reported previously;1 our regimen approximates the normal tempo of puberty (unpublished data). The
starting dose was 0.2 mg/mo, and the dose was increased at
6-month intervals to 0.4, 0.6, and 0.8 mg/mo. Two of the patients
dropped out of the study after 18 months of treatment; thus, only
7 patients were left at the end of the 2-year study. In addition to
height and growth rate, we evaluated bone age and Bayley–
Pinneau predicted height,16 as well as pubertal milestones.
We compared the growth in these patients with that in girls
with TS in the National Cooperative Growth Study database who
were treated with routine estrogen therapy. From 152 patients in
the database in whom estrogen had been started at 12 to 15 years
of age and who also had been treated with GH for at least 6
months, we matched a subgroup of 37 on the age at which the
estrogen was started and on the duration of GH treatment before
estrogen. Routine estrogen treatment in the 11 patients in the
database taking equine estrogens was #0.15 mg every other day in
2 patients, 0.3 mg every other day in 4 patients, and $0.3 mg daily
in 5 patients.
RESULTS
The mean age at the initiation of estrogen therapy
was 12.9 years in both groups. The mean duration of
GH therapy before estrogen therapy was 2.9 years in
the patients who were treated with depot estradiol
and 3.0 years in those who were treated with routine
estrogen. The growth rate increased during the first 6
months of treatment in 7 of the 9 patients who were
given depot estradiol. In 4 of these 7, it remained
above the pretreatment rate at 1 year. On average,
the growth rate increased slightly during the first 6
months, was very close to baseline at 1 year, and then
gradually decreased to below the baseline rate. The
mean height of the girls who were treated with depot
estradiol increased by 9.0 cm at 18 months and by
12.7 cm at 2 years.
The growth rate in the girls who were treated with
DISCUSSION
TABLE 1. Growth Rates in TS With Concurrent GH and Depot
Estradiol or Routine Estrogen Treatment
Growth Rate (cm/y)
GH 1 Estrogen
GH
Month
0
6
12
18
24
Depot
5.7 6 0.9 6.9 6 0.8 6.2 6 0.8 5.0 6 0.8 3.8 6 0.7*
estradiol
Routine
6.0 6 0.2 5.6 6 0.2* 5.1 6 0.2* 4.6 6 0.2* 4.0 6 0.1*
estrogen
Values are mean 6 SEM. n 5 9 through month 18, 7 thereafter
(depot estradiol); 37 through month 18, 28 thereafter (routine
estrogen).
* P , .05 vs month 0.
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014
SUPPLEMENT
487
The importance of this study is that it suggests that
the final height of patients with TS who are treated
with GH is increased by using very low doses of
systemic estradiol, rather than routine estrogen therapy, to induce puberty. The gain seems equivalent to
that achieved with 1 year of GH therapy alone. A
trial with a larger number of patients will be required
to confirm these data and to determine the long-term
consequence of this intervention strategy on bone
mineralization.
ACKNOWLEDGMENTS
This study was supported in part by US Public Health Service
Grant RR-00055 to Dr Rosenfield and in part by Genentech, Inc,
South San Francisco, CA (a grant of growth hormone and statistical support).
7.
8.
9.
10.
11.
12.
REFERENCES
1. Rosenfield RL, Fang VS. The effects of prolonged physiologic estradiol
therapy on the maturation of hypogonadal teenagers. J Pediatr. 1974;85:
830 – 837
2. Zachmann M, Prader A, Sobel E, et al. Pubertal growth in patients with
androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. J Pediatr. 1986;108:694 – 697
3. Mauras N, Rogol AD, Veldhuis JD. Increased hGH production rate after
low-dose estrogen therapy in prepubertal girls with Turner’s syndrome.
Pediatr Res. 1990;28:626 – 630
4. Smith E, Boyd J, Frank G, et al. Estrogen resistance caused by a mutation
in the estrogen-receptor gene in a man. N Engl J Med. 1994;331:
1056 –1061
5. Crawford J. Treatment of girls with estrogen. Pediatrics. 1978;62(suppl):
1189 –1195
6. Blizzard R, Thompson R, Baghdassarian A, Kowarski A, Migeon C,
Rodriguez A. The interrelationship of steroids, growth hormone, and
13.
14.
15.
16.
17.
other hormones on pubertal growth. In: Grumbach M, Grave G, Mayer
F, eds. Control of the Onset of Puberty. Airlie, VA: Wiley & Sons; 1972:
342–359
Attie KM, Chernausek S, Frane J, Rosenfeld RG. Growth hormone use
in Turner syndrome: a preliminary report on the effect of early vs
delayed estrogen. In: Albertsson-Wikland K, Ranke M, eds. Turner
Syndrome in a Life-span Perspective. New York, NY: Amsterdam/New
York; 1995:175–181
Lieberman S. Are the differences between estradiol and other estrogens,
naturally occurring or synthetic, merely semantical? J Clin Endocrinol
Metab. 1996;81:850 – 853
Jensen E, Jacobson H, Flesher J, et al. Estrogen receptors in target
tissues. In: Nakao T, Pincus G, Tait J, eds. Steroid Dynamics. New York,
NY: Academic Press; 1966:133–157
Korenman S. Comparative binding affinity of estrogens and its relation
to estrogenic potency. Steroids. 1969;13:163–177
Hirai S, Hussain A, Haddadin M, Smith R. First-pass metabolism of
ethinyl estradiol in dogs and rats. J Pharm Sci. 1981;70:403– 406
Laufer L, DeFazio J, Lu J, et al. Estrogen replacement therapy by
transdermal estradiol administration. Am J Obstet Gynecol. 1983;146:
533–540
Clemmons D, Underwood L, Ridgway E, Kliman B, Kjellberg R, Van
Wyk J. Estradiol treatment of acromegaly: reduction of immunoreactive
somatomedin-C and improvement of metabolic status. Am J Med. 1980;
69:571–575
Ross J, Cassorla F, Skerda M, Valk I, Loriaux D, Cutler GJ. A preliminary study of the effect of estrogen dose on growth in Turner’s syndrome. N Engl J Med. 1983;309:1104 –1106
Rosenfield RL, Fang VS, Dupon C, Kim MH, Refetoff S. The effects of
low doses of depot estradiol and testosterone in teenagers with ovarian
failure and Turner’s syndrome. J Clin Endocrinol Metab. 1973;37:574 –580
Bayley N, Pinneau S. Tables for predicting adult height from skeletal
age: revised for use with the Gruelich-Pyle hand standards. J Pediatr.
1952;40:432– 441
Rosenfeld RG, Frane J, Attie K, et al. Six-year results of a randomized
prospective trial of human growth hormone and oxandrolone in Turner
syndrome. J Pediatr. 1992;121:49 –55
The Psychological Consequences of Turner Syndrome and Review of the
National Cooperative Growth Study Psychological Substudy
Patricia T. Siegel, PhD*; Richard Clopper, ScD‡; and Brian Stabler, PhD§
ABSTRACT. Objective. To present longitudinal data
on the psychological profile of a cohort of girls with and
without Turner syndrome (TS) treated for 3 years with
growth hormone (GH).
Methods. Among a sample of 283 children with short
stature, 37 girls with TS were recruited at 27 US medical
centers. Of the original cohort, 22 girls with TS, 13 girls with
isolated growth hormone deficiency (GHD), and 12 girls
with idiopathic short stature were followed through 3 years
From the *Department of Psychiatry and Behavioral Neurosciences, Wayne
State University School of Medicine, Detroit, Michigan; the ‡Department of
Psychiatry, State University of New York at Buffalo, Buffalo, New York; and
the §Department of Psychiatry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina.
This work was presented in part at the National Cooperative Growth Study
Eleventh Annual Investigators Meeting, September 25–28, 1997, Washington, DC.
Received for publication Feb 6, 1998; accepted Mar 20, 1998.
Address correspondence to Patricia T. Siegel, PhD, Department of Child
Psychiatry and Psychology, Children’s Hospital of Michigan, 3901 Beaubien
Blvd, Detroit, MI 48201.
PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Academy of Pediatrics.
488
SUPPLEMENT
of GH therapy. All were school-age, were below the 3rd
percentile for height, had low growth rates, and were naive
to GH therapy. Psychological tests (the Wide Range
Achievement Test and the Slosson Intelligence Test) were
administered to the clinical groups within 24 hours of their
first GH injection and yearly thereafter. Control subjects
were 25 girls with normal stature matched for age and
socioeconomic status, who were tested only at baseline.
One parent of each subject also completed the Child Behavior Checklist for that subject.
Results. At baseline, the clinical groups had more
internalizing behavioral problems, had fewer friends,
and participated in fewer activities than did the control
subjects. The groups did not differ in mean IQ or
academic achievement, but the TS group did have
more problems in mathematics achievement. Height
and growth rate significantly increased in the clinical
groups over the 3 years of GH therapy, but IQ and
achievement scores did not. Significant linear reductions were noted in both Internalizing and Externalizing Behavior Problems after GH treatment, with the TS
group having fewer behavior problems before and after GH treatment than did the GHD–idiopathic short
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014
Optimizing Estrogen Replacement Treatment in Turner Syndrome
Robert L. Rosenfield, Nancy Perovic, Nancy Devine, Nelly Mauras, Tom Moshang,
Allen W. Root and Judy P. Sy
Pediatrics 1998;102;486
Updated Information &
Services
including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/102/Supplement_
3/486.full.html
Citations
This article has been cited by 1 HighWire-hosted articles:
http://pediatrics.aappublications.org/content/102/Supplement_
3/486.full.html#related-urls
Subspecialty Collections
This article, along with others on similar topics, appears in the
following collection(s):
Endocrinology
http://pediatrics.aappublications.org/cgi/collection/endocrinol
ogy_sub
Puberty
http://pediatrics.aappublications.org/cgi/collection/puberty_su
b
Pharmacology
http://pediatrics.aappublications.org/cgi/collection/pharmacol
ogy_sub
Therapeutics
http://pediatrics.aappublications.org/cgi/collection/therapeutic
s_sub
Permissions & Licensing
Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pediatrics.aappublications.org/site/misc/Permissions.xht
ml
Reprints
Information about ordering reprints can be found online:
http://pediatrics.aappublications.org/site/misc/reprints.xhtml
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright © 1998 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014